GIST patients see new clinical trials

Gleevec, SU11248 will be joined by other new therapies in near future

By Jerry Call with Norman Scherzer

Editor’s note: Jerry Call is the science coordinator for the Life Raft Group, and Norman Scherzer is the group’s executive director.

The remarkable success of Gleevec for treating GIST has introduced GIST patients to the world of molecularly targeted therapy for cancer. It has also set a very high bar for other treatments.

Gleevec has also introduced many patients in the Life Raft Group to clinical trials. I am not sure what the percentages are, but I am confident that many more Life Raft Group patients participate in clinical trials now than in the pre-Gleevec era.

As wonderful as Gleevec is, some GIST patients do not respond to it and some eventually stop responding to it. We recommend that whenever possible, patients failing Gleevec participate in a clinical trial. There are many advantages to this such as:
• A medical team that is familiar with GIST.
• Clinical trials move GIST research forward.
• Medical treatment and monitoring are usually better.
• This is generally the only way to access drugs that have not yet been approved.

Like many with cancer, GIST patients join clinical trials in a bid to survive, and often do not have the time to wait for more conclusive results.

We do recognize however, that participation in clinical trials is difficult, if not impossible, for some patients. Some may not be eligible. Some live in places where clinical trials are limited. With this in mind we have attempted to list some current options that might be considered.

Keep in mind this disclaimer: We are not doctors and information we offer should be discussed with your doctor. Because patients may be trying to survive the lethal time gap of clinical research, we have pushed the envelope of verifiable information. Extra caution is therefore needed and we invite the clinical researchers to comment or clarify.

Sugen SU11248

More is known about the results of the Sugen SU11248 clinical trial than any other alternative to Gleevec. About two-thirds of patients that fail Gleevec respond to SU11248. It is by far the best-understood option and is the current clinical trial of choice for patients failing Gleevec. Failure to respond to Gleevec has been a prerequisite for acceptance into this trial.

This trial requires staying in Boston (Dana-Farber Cancer Institute) or New York (Memorial Sloan-Kettering Cancer Center) for a considerable time, due in part to the extensive testing required for phase I patients.

To date, 11 of 18 patients (61 percent) have exhibited disease regression or stable disease (2-28 percent tumor reduction) lasting more than four months, and objective anatomic responses continue to evolve over time.

It is our understanding that this trial is now moving into phase II at Dana- Farber. The initial period patients must spend there should be less for phase II patients than phase I patients. Phase II trials may start at other locations in the near future.

The following message was sent June 6 to the Life Raft Group from Dr. George Demetri:

“Dear members of the GIST community,
“Now that the ASCO meeting is over, we can all more fully discuss the current state of the art in the newer options for GIST patients.

“As you have probably heard, we are planning to move the SU11248 treatment option quickly into a global clinical trial. This will represent a logistical challenge, since we would ideally wish to do this very, very fast, and we will be drawing up these plans soon. In the meanwhile, our plan is to continue the current clinical trial which is open here in Boston at Dana-Farber Cancer Institute and was also recently opened in New York City at the Memorial Sloan- Kettering Cancer Center.

“We have heard that Pfizer is supportive of our plans, and for that we are most grateful.

“Other promising options also exist and will be explored in a variety of strategic clinical trials. However, the SU11248 is by far the most wellexplored other option for patients with GIST at this time.

“Thank you all for the support that you have shown to our team and to the investigative teams interested in GIST worldwide. This sort of collaboration should enable the research to continue to move forward as rapidly as possible and advance the field with positive therapeutic results and with a greater understanding of the directions we should take in the future.”

We wish to thank Demetri, Pfizer, and all of the other behind the scene people involved in organizing these trials. We hope that trials will be globally available since this drug seems so promising.

While SU11248 is the most proven drug for those that fail Gleevec, several other clinical trials have either started or will start in the near future for GIST. The first of these is the combination of Gleevec and RAD001 (RAD).

RAD001 plus Gleevec:

Both RAD001 and Gleevec are manufactured by Novartis. RAD001 is an mTOR inhibitor that may improve the effectiveness of Gleevec. mTOR is a downstream target in the AKT pathway. AKT is a survival pathway that is activated by KIT and many other receptors. It is hoped that simultaneous inhibition of KIT and mTOR will result in increased effectiveness over Gleevec alone.

Trials have already started in Belgium and at Dana-Farber. Patients accepted at Dana-Farber are those who stopped responding to both Gleevec and Sugen. In Belgium, there is no Sugen trial hence patients selected are those who stopped responding to Gleevec.

It has long been speculated that GIST — and most cancers in general — will eventually be treated with a “cocktail” of various drugs. This is the first such combination to come to clinical trials for GIST.

PKC787

This is another Novartis drug. It is an inhibitor of KIT, PDGFR, and VEGFR. Although we are not aware of any current trials solely for GIST, the targets of this drug would be relevant to GIST. On paper this drug appears to be similar to SU11248.

AMG706

This drug was developed by Amgen. Phase I trials will be at the John Wayne Cancer Institute in Santa Monica, California and at M.D. Anderson Cancer Center in Houston, Texas. We have heard that this drug is similar to SU11248, however, we have not verified the targets of this drug. These early phase I trials are open to many different types of cancer besides GIST.

PKC412 plus Gleevec:

This trial has not started yet. PKC412 is another Novartis drug. It is an inhibitor of KIT, as well as protein kinase C (PKC); however PKC is probably the main target of this drug. Recently it has been suggested (Duensing et al, 2003) that protein kinase C theta is constitutively activated in all GISTs including those which are c-kit negative.

A phase I trial is anticipated at Oregon Health & Science University in Portland this October. Details are lacking, but our early understanding is that PKC412 may be given together with Gleevec in this trial.

Gleevec + Gentasense

Genta Inc. makes Gentasense, an antisense drug. These drugs are small, chemically modified strands of DNA. Gentasense inhibits the production of bcl-2. Bcl-2 is an anti-apoptosis protein. In one recent study, 11 of 11 GIST tumors expressed bcl-2.

It is speculated that inhibition of bcl- 2 might tip the balance of proapoptosis/ anti-apoptosis proteins toward apoptosis. Apoptosis is a form of controlled cell death, a type of cellular suicide where the cell issues its own death warrant.

Our understanding is that a phase I trial with this combination may start soon at Dana-Farber.

An overview of antisense drugs can be found at the Genta Web site:http:// www.genta.com/genta/Products/ antisense.html

The following two trials are much more speculative than the preceding trials. They are listed because they use somewhat novel approaches that differ from the preceding trials in their mechanisms of action:

Carboxyamidotriazole (CIA)

CIA is an anti-angiogenic drug being developed by the National Cancer Institute. It inhibits calcium (Ca2) influx into the cell. It addition to being antiangiogenic, inhibition of calcium influx may also be cytotoxic to some types of cancer cells.

This drug is in phase I trials for solid tumors. This trial also includes the more traditional chemotherapy, Paclitaxel. It is also in phase III trials for patients with non-small cell lung cancer.

One of the potential advantages of this drug is that, in theory, it might work against several of the known mechanisms of resistance of Gleevec treatment of GIST. These include mutations that render Gleevec ineffective. One concern with this trial is that we are not aware of any pre-clinical evidence of in-vitro effectiveness in GIST tumor cells.

17-AAG

This is a benzoquinoid ansamycin antibiotic, currently in clinical trials, which binds to heat shock protein 90 (hsp90), causing de-stabilization of various hsp90-dependent kinases involved in proliferation and survival of malignant cells, (including KIT).

17-AAG, by a novel mechanism, may be effective in the treatment of mastocytosis. In addition, 17-AAG may have a role in the treatment of other diseases where c-kit plays a crucial role in pathogenesis, including GIST, mast cell leukemia, some types of acute myelogenous leukemia and testicular cancer.

One of the theoretical advantages of targeting hsp90 is that GIST tumors that harbor mutations outside of exons 9 and 11 might still be sensitive to the effects of hsp90 inhibition.

Our concerns with this drug (and hsp90 inhibitors in general) are:
• Limited oral bioavailability and solubility. Second generation HSP90 inhibitors may be designed to overcome some of the drawbacks of 17- AAG. They could also be engineered to target specific functions of hsp90, which may not only provide greater molecular selectivity and clinical benefit but may also increase understanding of the complex functions of this molecular chaperone.
• The drug is difficult to use, with an unsatisfactory formulation, and is currently limited in its availability.
• It does not appear to be very specific. Drugs that do have very specific targets (like Gleevec) tend to have fewer side effects and less toxicity.